Prodrug design: an opportunity to improve bioavailability

Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their metabolization into pharmacologically active drugs after administration, offering opportunities to optimize the pharmaceutical property to improve bioavailability.

Approximately 10% of all marketed drugs worldwide can be considered Prodrugs, targeting several therapeutic fields, such as Oncology.

Among the scope of drug delivery systems for modification, several chemical classes are known, such as: polymers, lipids, amino acids, carbohydrates, amines, alcohols, phytophenols.

As an illustration, Polymer-Drug Conjugates (PDCs), or polymeric prodrugs, are one of the drug delivery tools in nanomedicine in which one or more therapeutic agents are covalently bound to a polymeric carrier. This conjugation strategy has mostly been applied for potent anti-tumor drugs with high cytotoxicity and poor solubility. For example, the conjugation of Paclitaxel palmitate with PLGA, proved to be efficient against the Lung Cancer in the Mouse Model.

In the case of lipid-based prodrugs, a broad range of lipid structures have been linked to anticancer drugs, thus showing the flexibility and the versatility of prodrugs design strategy.

Some valuable physicochemical improvements have been demonstrated over conventional treatments.

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Prodrug synthesis has several advantages over the parent active drug:

• Improved permeability: Knowing that formulation techniques can be challenging for enhancing permeability, Prodrugs provide the opportunity to be considered as a new chemical entity (NCE).
• Improved solubility: Prodrug synthesis can improve the solubility of poorly soluble APIs by modifying their chemical structure, making them more easily absorbed by the body.
• Increased stability: Prodrugs can be designed to be more stable than the corresponding active compound, which can increase their shelf life and reduce the need for low temperature storage.
• Improved pharmacokinetics: Prodrugs can be designed to enhance the pharmacokinetic properties of the parent drug, such as absorption, distribution, metabolism, and excretion. This can lead to improved efficacy and reduced toxicity.
• ?Targeted delivery: Prodrugs can be designed to deliver the active compound to a specific site in the body, such as the brain or tumor tissue, while minimizing exposure to healthy tissue.
• ?Reduced side effects: Prodrug synthesis can reduce the side effects associated with active drugs by modifying their chemical structure or releasing the active compound more slowly, resulting in a more gradual and sustained therapeutic effect.

Overall, Prodrug synthesis is a powerful tool for improving the therapeutic potential of drugs and can lead to better patient outcomes and reduced healthcare costs.

For further information, do not hesitate to consult the following reviews:

(1)???J. Nicolas, Drug-Initiated Synthesis of Polymer Prodrugs: Combining Simplicity and Efficacy in Drug Delivery, Chem. Mater. 2016, 28, 1591?1606.

(2)???D. Braatz,?M. Cherri,?M. Tully,?M. Dimde,?G. Ma,?E. Mohammadifar,?F. Reisbeck,?V. Ahmadi,?M. Schirner,?R. Haa, Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications, Angew. Chem. Int. Ed. 2022, 61, e202203942.

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